CDK1通过FGFR3/HIF-1途径调控糖酵解信号通路促进膀胱癌恶性增殖的机制

成纤维细胞生长因子受体3（FGFR3）是膀胱癌中高频突变（≈45%）的驱动癌基因，也是近期首个批准用于膀胱癌治疗的药物靶点，但目前对其下游信号通路的探索尚不足。我们转录组学预实验首次发现HIF-1是FGFR3下游的关键转录因子，并证明HIF-1促进了FGFR3依赖的膀胱癌细胞的糖酵解途径。为了明确膜蛋白FGFR3如何调控核内的HIF-1转录因子，前期采用磷酸化蛋白质组学筛选了受FGFR3调控的下游激酶进而锚定CDK1分子，且发现抑制CDK1的活性可显著影响膀胱癌细胞的增殖。但尚未证实FGFR3/CDK1/HIF-1三者间的上下游逐级调控关系，亦不清楚该通路在膀胱癌中介导的生物学效应。本项目假设CDK1通过FGFR3/HIF-1途径调控糖酵解信号通路促进膀胱癌的增殖，并拟从体内和体外模型予以论证。该研究将解析全新的FGFR3信号通路和其致癌机制，并探索CDK1成为膀胱癌治疗新靶点的可能。

Fibroblast growth factor receptor 3 (FGFR3) is one of the most frequently mutated oncogenes in bladder cancer (BCa) and anti-FGFR3 therapy has been recently approved as the first-in-class targeted therapy to treat BCa. However, those dysregulated signaling pathways,induced by mutated and constitutively activated FGFR3 receptor, are largely unknown in BCa. In this project, we aimed to decipher the FGFR3-driven signaling pathways in BCa by applying multi-omics methodology: 1) our transcriptomic data from in vitro system has highlighted hypoxia-inducible factor (HIF-1) as one of the key transcription factor (TF) modulated by FGFR3, which was also confirmed in our recently developed transgenic mice model with FGFR3-overexpression; 2) the preliminary results showed that FGFR3/HIF-1 axis was likely involved in promoting glycolysis; 3) the phospho-proteomic data, achieved by mass spectrometry, has identified cyclin-dependent kinase 1 (CDK1) as a candidate kinase that may intermediate the regulation between FGFR3 and HIF-1. Finally, inhibition of either HIF-1 or CDK1 impacted BCa-derived cell viability, implying HIF-1 and CDK1 as potential therapeutic targets in BCa. Taken together these preliminary data, we proposed a new FGFR3-driven signaling pathway, namely FGFR3/CDK1/HIF-1/glycolysis, that would promote the proliferation of BCa cells. In future, we need to further resolve those issues through in vitro and in vivo experiments: how FGFR3 regulates CDK1 enzyme activity and HIF-1 transcriptional activity? through which mechanism CDK1 stablizes HIF-1? whether FGFR3/CDK1/HIF-1 axis favors glycolysis? Hopefully, our study would help better clarify the role of FGFR3 and its signaling cascades during BCa tumorigenesis and propose potential therapeutic targets for BCa, such as CDK1.